Underlying disease

Abnormalities of LFT may relate to underlying liver disease in patients receiving parenteral nutrition rather than the effects of the parenteral nutrition itself, although the effects of the latter may exacerbate the former. It is also important to be aware that treatment of the underlying disease may influence liver function as a result of drug hepatotoxicity. Patients with inflammatory bowel disease may have occult sclerosing cholangitis with histological evidence of steatosis or pericholangitis in the presence of normal LFT⁽Reference Nightingale¹⁶⁾. Patients who have short-bowel syndrome as a result of mesenteric infarction may also have underlying insulin resistance, dyslipidaemia and non-alcoholic fatty liver disease. It has been shown that in adults receiving long-term parenteral nutrition the presence of pre-existing liver disease is associated with a threefold increased risk of chronic cholestasis⁽Reference Cavicchi, Beau, Crenn, Degott and Messing¹⁰⁾.

Sepsis

As mentioned earlier, the presence of sepsis is an important precipitant of cholestasis in neonates and of abnormal LFT in adults receiving short-term parenteral nutrition. Bacterial overgrowth is relatively common in both children and adults with intestinal failure as a result of intestinal stasis. It has been proposed that bacterial overgrowth may be causative in the development of liver dysfunction in patients receiving parenteral nutrition because of bacterial translocation and the effects of bacterial endotoxin and also because of the generation of secondary bile salts such as lithocholic acid as a result of bacterial dehydroxylation of chenodeoxycholic acid⁽Reference Quigley, Marsh, Shaffer and Markin⁴⁾. Recent human studies support the concept of bacterial translocation previously only seen in animal models⁽Reference Reddy, MacFie, Gatt, Macfarlane-Smith, Bitzopoulou and Snelling¹⁷⁾, and experiments performed in animals suggest that the effects of bacterial endotoxins on the liver may be mediated by cytokines such as TNFα⁽Reference Pappo, Bercovier, Berry, Gallilly, Feigin and Freund¹⁸⁾. The concept that bacterial overgrowth causes hepatic dysfunction via production of secondary bile acids has less support in human subjects, particularly since potentially-therapeutic exogenous bile salts such as ursodeoxycholic acid (UCDA) can also be metabolised to lithocholic acid⁽Reference Buchman, Iyer and Fryer¹⁹⁾.

Intestinal anatomy

PNALD has been shown to be related to small intestinal length in a number of studies⁽Reference Luman and Shaffer^6, Reference Ito and Shils^8, Reference Cavicchi, Beau, Crenn, Degott and Messing¹⁰⁾. One study has reported that a small intestinal length of <1 m is associated with abnormal LFT in adults receiving long-term parenteral nutrition⁽Reference Luman and Shaffer⁶⁾, while another study has reported an increased risk of chronic cholestasis in adults with a small intestinal length of <0·5 m⁽Reference Cavicchi, Beau, Crenn, Degott and Messing¹⁰⁾. Some authors have postulated that short-bowel syndrome predisposes to liver dysfunction as a result of impairment of enterohepatic bile salt circulation and abnormal bile acid metabolism⁽Reference Cavicchi, Beau, Crenn, Degott and Messing¹⁰⁾. Others have argued that bowel length may simply be a surrogate marker of parenteral energy requirement⁽Reference Luman and Shaffer⁶⁾. It is of interest that LFT have been noted to improve after isolated small intestinal transplantation, even in a small number of cases in which there was biopsy-proven hepatic fibrosis⁽Reference Langrehr, Reilly, Banner, Warty, Lee and Schraut^20, Reference Lauro, Zanfi and Ercolani²¹⁾.

Lack of enteral nutrition

Reduced enteral nutrition is intimately associated with an increased reliance on parenteral nutrition, and so it is very difficult to ascertain whether the increased risk of liver dysfunction seen in individuals with very little oral intake is a result of the lack of enteral nutrition, or the effects of parenteral feeding. Fasting coupled with total parenteral nutrition has been shown to reduce the secretion of a number of gastrointestinal hormones, including gastrin, motilin, pancreatic polypeptide, insulinotropic polypeptide and glucagon⁽Reference Greenberg, Wolman, Christofides, Bloom and Jeejeebhoy²²⁾. This reduction in secretion may reduce intestinal motility, promoting bacterial overgrowth, and may predispose to biliary stasis⁽Reference Greenberg, Wolman, Christofides, Bloom and Jeejeebhoy²²⁾. It has been suggested that total parenteral nutrition induces small intestinal mucosal atrophy, which in turn allows increased bacterial translocation across the gut mucosal barrier. However, although total parenteral nutrition induces marked mucosal atrophy in rodent models, the effect in human subjects is much less dramatic and the results of clinical studies are mixed⁽Reference Alpers^23–Reference Sedman, MacFie, Palmer, Mitchell and Sagar²⁵⁾.

Nutrient deficiency

Individuals with kwashiorkor, resulting from severe protein–energy malnutrition, develop hepatic steatosis because there is insufficient protein for the manufacture of VLDL, which is needed for hepatic TAG export⁽Reference Cook and Hutt²⁶⁾. However, patients receiving parenteral nutrition should receive adequate amino acids for VLDL synthesis. Similarly, inadequate supply of linoleic acid may result in essential fatty acid deficiency, which is also associated with steatosis⁽Reference Richardson and Sgoutas²⁷⁾. Since the majority of parenteral lipid infusions are manufactured using soyabean oil, which is rich in linoleic acid, essential fatty acid deficiency is rare, unless fat-free parenteral regimens are employed in individuals with little or no enteral lipid intake.

There has been recent interest in the possibility that deficiencies of a number of methionine metabolites, such as carnitine, choline and taurine, may be responsible for both steatosis and cholestasis in patients receiving parenteral nutrition. Orally-ingested methionine can be converted to these metabolites via hepatic transulfuration pathways, although these pathways are underdeveloped in premature infants⁽Reference Vina, Vento, Garcia-Sala, Puertes, Gasco, Sastre, Asensi and Pallardo²⁸⁾. However, methionine administered parenterally to the systemic circulation rather than to the portal circulation is also transaminated to mercaptans, hence reducing the synthesis of carnitine, choline and taurine⁽Reference Chawla, Berry, Kutner and Rudman²⁹⁾. Carnitine, choline and taurine are not routinely administered as part of parenteral formulations and there is evidence that levels are low in individuals receiving parenteral nutrition⁽Reference Bowyer, Fleming, Ilstrup, Nelson, Reek and Burnes^30–Reference Vinton, Laidlaw, Ament and Kopple³⁴⁾.

Carnitine is involved in the transport of long-chain fatty acids across the mitochondrial membrane so that they can undergo oxidation. In deficiency states in which carnitine levels are very low (<10% normal levels) hepatic steatosis can develop⁽Reference Karpati, Carpenter, Engel, Watters, Allen, Rothman, Klassen and Mamer³⁵⁾. Although plasma carnitine levels are low in patients receiving parenteral nutrition, they are about 50% normal levels and so considerably higher than levels in patients with congenital or acquired deficiency⁽Reference Bowyer, Fleming, Ilstrup, Nelson, Reek and Burnes^30, Reference Moukarzel, Dahlstrom, Buchman and Ament^31, Reference Karpati, Carpenter, Engel, Watters, Allen, Rothman, Klassen and Mamer³⁵⁾. There is limited evidence to suggest an inverse relationship between carnitine levels and ALP in patients receiving parenteral nutrition⁽Reference Berner, Larchian, Lowry, Nicroa, Brennan and Shike³⁶⁾. However, intervention studies have failed to show any benefit of parenteral carnitine supplementation in patients receiving long-term parenteral nutrition in relation to hepatic abnormalities⁽Reference Bowyer, Miles, Haymond and Fleming³⁷⁾.

Choline, like carnitine, is normally synthesised from methionine. Levels are low in >90% of patients receiving parenteral nutrition⁽Reference Buchman, Moukarzel, Jenden, Roch, Rice and Ament³⁸⁾ as a result of the abnormal metabolism described earlier and the lack of choline in standard parenteral formulations. Choline is required for the synthesis of VLDL and hence hepatic TAG export. Choline deficiency results in impaired hepatic TAG secretion and subsequent steatosis⁽Reference Buchman, Moukarzel, Jenden, Roch, Rice and Ament³⁸⁾. Choline deficiency in patients receiving parenteral nutrition has been shown to correlate with elevated transaminase levels and steatosis in both adults and children receiving parenteral nutrition⁽Reference Buchman, Moukarzel, Jenden, Roch, Rice and Ament^38, Reference Buchman, Sohel and Moukarzel³⁹⁾. Small studies have shown that both parenteral choline supplementation and high-dose oral supplementation can reverse these abnormalities⁽Reference Buchman, Dubin, Jenden, Moukarzel, Roch, Rice, Gornbein, Ament and Eckhert^40, Reference Buchman, Ament, Sohel, Dubin, Jenden, Roch, Pownall, Farley, Awal and Ahn⁴¹⁾.

Taurine is important for bile salt conjugation, particularly in preterm infants. It promotes bile flow and attenuates the cholestatic effects of secondary bile salts such as lithocholate⁽Reference Belli, Roy, Fournier, Tuchweber, Giguere and Yousef^42, Reference Dorvil, Yousef, Tuchweber and Roy⁴³⁾. Taurine deficiency in neonates is associated with cholestatic liver disease⁽Reference Cooper, Betts, Pereira and Ziegler⁴⁴⁾ and there is some evidence that this condition can be prevented by parenteral taurine supplementation⁽Reference Heird, Dell, Helms, Greene, Ament, Karna and Storm^45, Reference Spencer, Yu and Tracy⁴⁶⁾. Studies in adults have shown that both plasma and biliary taurine levels are low⁽Reference Schneider, Joly, Gehrardt, Badran, Myara, Thuillier, Coudray-Lucas, Cynober, Trivin and Messing⁴⁷⁾, probably as a result of a combination of reduced synthesis via hepatic transulfuration pathways coupled with an increased loss of bile acids associated with ileo-colonic resection. Supplementation in adults with short-bowel syndrome has been shown to improve plasma but not biliary taurine levels, this change being accompanied by an improvement in plasma transaminase concentrations⁽Reference Schneider, Joly, Gehrardt, Badran, Myara, Thuillier, Coudray-Lucas, Cynober, Trivin and Messing⁴⁷⁾.

It has been proposed that individuals receiving parenteral nutrition may be deficient in antioxidants, in particular vitamin E and Se⁽Reference Nightingale¹⁶⁾. Increased oxidative stress might predispose to lipid peroxidation of hepatic lipid stores resulting in inflammation and steatohepatitis⁽Reference Buchman, Iyer and Fryer¹⁹⁾. Some experiments using animal models suggest that antioxidants such as glutathione may attenuate the hepatic dysfunction induced by parenteral feeding⁽Reference Hong, Wu and Cai⁴⁸⁾. However, although markers of oxidative stress are raised in adults receiving parenteral nutrition, there is little evidence that oxidative damage is increased despite infusion of soyabean-based lipid infusions rich in PUFA⁽Reference Schepens, Roelofs, Peters and Wanten⁴⁹⁾. Studies in children suggest that the occurrence of parenteral nutrition-associated cholestasis is independent of oxidant load⁽Reference Lavoie, Chessex, Gauthier, Levy, Alvarez, St-Louis and Rouleau⁵⁰⁾. In addition, there is little evidence that antioxidant levels are depleted in patients receiving parenteral nutrition, and vitamin E is commonly added to intravenous lipid emulsions⁽Reference Buchman, Iyer and Fryer¹⁹⁾.

Nutrient toxicity

Early parenteral nutrition formulations contained large amounts of energy supplied as glucose, and the total glucose content often exceeded the maximum glucose oxidation rate. It is likely that this factor partly explains the high incidence of steatosis seen in these early studies⁽Reference Lindor, Fleming, Abrams and Hirschkorn²⁾. Glucose infusion at rates of >5 mg/body weight (BW) per min have been demonstrated to result in steatosis in human subjects⁽Reference Burke, Wolfe, Mullany, Mathews and Bier⁵¹⁾. High glucose infusion rates result in high plasma glucose concentrations, which in turn stimulate insulin release. High plasma insulin concentrations stimulate hepatic lipogenesis and the production of acylglycerol from glucose while concomitantly inhibiting mitochondrial fatty acid oxidation⁽Reference Li, Nussbaum, Teague, Gapen, Dayal and Fischer⁵²⁾. This process results in a build up of TAG within the hepatocytes. The adverse effects of insulin hypersecretion may also explain why continuous parenteral nutrition infusion is associated with a greater extent of hepatic dysfunction than cyclic infusion. Allowing ≥8 h each day without parenteral glucose infusion has been shown to lower insulin levels and improve LFT⁽Reference Hwang, Lue and Chen⁵³⁾. It was initially thought that the failure of the liver to secrete the excess TAG into the circulation was the result of inadequate amino acid content relative to carbohydrate content limiting adequate lipoprotein production⁽Reference Quigley, Marsh, Shaffer and Markin⁴⁾. However, steatosis has been shown to result from excessive glucose infusion even if amino acid intake is adequate⁽Reference Guglielmi, Boggio-Bertinet and Federico⁵⁴⁾. Interestingly, in animal models infusion of glucagon along with parenteral glucose has been shown to stimulate hepatic fatty acid release and attenuate steatosis⁽Reference Li, Nussbaum, McFadden, Gapen, Dayal and Fischer⁵⁵⁾.

The replacement of a proportion of glucose energy with parenteral lipid has been shown to reduce the incidence of steatosis⁽Reference Meguid, Akahoshi, Jeffers, Hayashi and Hammond⁵⁶⁾. However, excess lipid has also been demonstrated to result in hepatic complications. Very high parenteral lipid intakes of >4 g/kg BW per d may result in a fat-overload syndrome because of the inability of the reticulo-endothelial system to clear such large amounts of PUFA and phospholipid⁽Reference Bigorgne, Le Tourneau, Messing, Rio, Giraud, Molina, Audouin and Diebold⁵⁷⁾. An association between more-modest parenteral lipid intake and the incidence of both chronic cholestasis and advanced liver disease has also been demonstrated in adults⁽Reference Cavicchi, Beau, Crenn, Degott and Messing¹⁰⁾. In multivariate analysis parenteral intake of soyabean-based lipid emulsion of >1 g/kg BW per d has been shown to be associated with a relative risk of chronic cholestasis of 2·3 and a relative risk of advanced liver disease (fibrosis or cirrhosis on liver biopsy) of 5·5⁽Reference Cavicchi, Beau, Crenn, Degott and Messing¹⁰⁾. The exact mechanism behind this effect is unclear. It has been postulated that lipid overloading of hepatic macrophages might impair phospholipid excretion into bile and cause intrahepatic cholestasis⁽Reference Cavicchi, Beau, Crenn, Degott and Messing¹⁰⁾. Other authors have suggested that lipid infusion may inhibit hepatic TAG release leading to accumulation in the liver⁽Reference Luman and Shaffer⁶⁾, or may cause accumulation of phytosterols⁽Reference Clayton, Whitfield and Iyer⁵⁸⁾. High plasma phytosterol concentrations have been documented in children but not in adults receiving parenteral lipid emulsions⁽Reference Clayton, Bowron, Mills, Massoud, Casteels and Milla⁵⁹⁾. There has been some suggestion that lipid infusions with a lower soyabean oil content may cause fewer hepatic complications, with studies showing a lower incidence of cholestasis in patients receiving lipid emulsions in which a proportion of the soyabean oil has been replaced with either medium-chain TAG⁽Reference Carpentier, Richelle, Haumont and Deckelbaum⁶⁰⁾ or MUFA⁽Reference Reimund, Arondel, Joly, Messing, Duclos and Baumann⁶¹⁾. There are also case reports of parenteral fish oil supplementation improving hepatic function in children⁽Reference Gura, Duggan, Collier, Jennings, Folkman, Bistrian and Puder⁶²⁾, although similar studies in adults have not been published.

A number of other components of parenteral infusions have been suggested to cause abnormal LFT in patients receiving parenteral nutrition. High amino acid content has been proposed to promote cholestasis in neonates⁽Reference Vileisis, Inwood and Hunt⁶³⁾, although as mentioned earlier there may also be a relative deficiency of certain amino acids in these individuals. Historically, tryptophan degraded in parenteral solutions containing NaHSO₄ to produce hepatotoxic metabolites⁽Reference Nightingale¹⁶⁾. However, NaHSO₄ is no longer used as a preservative in parenteral solutions. Similarly, Al has been shown to cause cholestasis in animal models but is not found in modern parenteral formulations in substantial quantities⁽Reference Klein⁶⁴⁾. Studies in children have shown an association between plasma Mn levels and cholestasis⁽Reference Fell, Reynolds, Meadows, Khan, Long, Quaghebeur, Taylor and Milla⁶⁵⁾. While it could be argued that since Mn is excreted via the biliary system this increase is simply a consequence of cholestasis rather than a cause, withdrawal of parenteral Mn improves hepatic function in children with high plasma levels⁽Reference Fell, Reynolds, Meadows, Khan, Long, Quaghebeur, Taylor and Milla⁶⁵⁾. Finally, Cu is also excreted via the biliary route and can accumulate in the liver if there is substantial cholestasis, which may exacerbate hepatic dysfunction⁽Reference Blaszyk, Wild, Oliveira, Kelly and Burgart⁶⁶⁾.

Treatment of non-nutritional causes

Given the importance of sepsis as a causative factor for PNALD, it is vital that every effort is made to reduce its incidence. Intra-abdominal sepsis should be treated using a procedure that is clinically appropriate, usually with a combination of antibiotics and/or minimally-invasive drainage procedures. It is also important to avoid central venous catheter-associated sepsis. To this end, studies in both adult and paediatric populations have demonstrated reduced rates of central venous catheter-associated sepsis in patients managed by specialist nutrition teams using strict aseptic techniques⁽Reference Kennedy and Nightingale^67, Reference Beath, Booth, Murphy, Buckels, Mayer, McKiernan and Kelly⁶⁸⁾. Efforts to reduce bacterial overgrowth have been more successful in neonates than in adults, suggesting a greater pathophysiological role in the former. Several small studies have suggested that antibiotics such as metronidazole and gentamicin may reduce the incidence of cholestasis in neonates receiving parenteral nutrition⁽Reference Spurr, Grylack and Mehta^69, Reference Kubota, Okada, Imura, Kawahara, Nezu, Kamata and Takagi⁷⁰⁾. Although a single study has suggested a benefit of metronidazole in adults, this study involved patients with active Crohn's disease and the reported effects of the antibiotic on ALP and γ-glutamyl transferase may well have been mediated via a beneficial effect on the activity of the Crohn's disease⁽Reference Capron, Gineston, Herve and Braillon⁷¹⁾. Other approaches that might possibly reduce bacterial translocation, such as increased dietary fibre intake and parenteral glutamine supplementation, have not to date been shown to have a beneficial effect on PNALD in human subjects.

Cholelithiasis is common in both adults and children receiving parenteral nutrition because of a combination of factors including reduced oral intake, ileal resection, weight loss and drug treatment⁽Reference Quigley, Marsh, Shaffer and Markin^4, Reference Nightingale¹⁶⁾. The incidence of biliary sludge in adults receiving parenteral nutrition has been estimated to approach 100% after >6 weeks of treatment⁽Reference Messing, Bories, Kunstlinger and Bernier⁷²⁾ and gallstones have been demonstrated to form in 45% of patients with short-bowel syndrome⁽Reference Nightingale, Lennard-Jones, Gertner, Wood and Bartram⁷³⁾. Although often asymptomatic, gallstones may cause cholecystitis or extrahepatic biliary obstruction with resultant abnormalities of LFT. Cholelithiasis in patients receiving parenteral nutrition can be prevented by encouraging enteral feeding and administration of cholecystokinin but may necessitate prophylactic cholecystectomy⁽Reference Nightingale¹⁶⁾.

Adjustments to parenteral nutrition

It is important not to overfeed patients receiving parenteral nutrition, given the deleterious effects of infusion of excess parenteral glucose and lipid described earlier. Both US and UK guidelines suggest a total daily energy intake of 105–146 kJ (25–35 kcal)/kg BW and a daily protein intake of 0·8–1·5 g/kg BW⁽Reference Buchman, Scolapio and Fryer^{74, 75)}, although more accurate assessment of BMR and energy requirements can be made by performing indirect calorimetry. Given that the majority of patients receiving long-term parenteral nutrition will continue to eat, it is also necessary to estimate enteral energy and protein absorption and reduce parenteral provision accordingly. In general, it is important to try to maximise enteral nutrition, although this approach may not always be possible. The oral route is preferable, although enteral-tube feeding can be employed and is often useful in infants. As well as countering the adverse effects of fasting described earlier and reducing parenteral requirements, enteral feeding promotes intestinal adaptation, which is of particular importance in infants for whom it may allow complete weaning from parenteral nutrition⁽Reference Wallis, Lloyd and Gabe⁷⁶⁾.

The optimal dose and type of parenteral lipid that should be provided to minimise hepatic dysfunction remains unclear. In patients who have no enteral intake some parenteral lipid is needed to prevent essential fatty acid deficiency⁽Reference Buchman, Scolapio and Fryer⁷⁴⁾. A linoleic acid intake of 2–4% total energy intake is adequate for this purpose⁽⁷⁷⁾ and, given the very high linoleic acid content of soyabean-based lipid emulsions, this level of intake is easily achievable. US guidelines suggest that parenteral lipid infusion should supply 20–30% total energy and daily intake should be <2·5 g/kg BW and ideally <1·5 g/kg BW⁽Reference Buchman, Scolapio and Fryer⁷⁴⁾. However, experimental data suggest that the intake of soyabean-based lipid should be <1·0 g/kg BW per d⁽Reference Cavicchi, Beau, Crenn, Degott and Messing¹⁰⁾. As previously discussed there is growing evidence that lipid emulsions containing a mixture of long-chain and medium-chain TAG⁽Reference Chan, McCowen and Bistrian⁷⁸⁾ (e.g. Lipofundin MCT/LCT^®; B Braun, Melsungen, Germany), emulsions with a high MUFA content⁽Reference Reimund, Arondel, Joly, Messing, Duclos and Baumann^61, Reference Vahedi, Atlan, Joly, Le Brun, Evard, Perennec, Roux-Haguenau, Bereziat and Messing⁷⁹⁾ (e.g. Clinoleic^®; Baxter, Maurepas, France) and emulsions containing fish oils⁽Reference Gura, Duggan, Collier, Jennings, Folkman, Bistrian and Puder⁶²⁾ (e.g. SMOF Lipid^®; Fresenius Kabi, Bad Homburg, Germany) may be preferable to soyabean-based emulsions in relation to hepatic complications, but the latter remain in widespread use. Further clinical trials are necessary to explore this area further.

Finally, cyclical rather than continuous parenteral nutrition should be administered to minimise the adverse effects of prolonged insulin hypersecretion. Allowing an 8 h break from parenteral nutrition has been shown to improve LFT and reduce insulin levels⁽Reference Hwang, Lue and Chen⁵³⁾. Cyclical parenteral nutrition also allows greater patient freedom, which may be associated with an improved quality of life in patients receiving long-term parenteral nutrition⁽⁷⁵⁾.

Pharmacological treatment

UDCA is an exogenous bile acid used in the management of a number of cholestatic conditions, including primary biliary cirrhosis and cholelithiasis, with the aim of promoting biliary flow. There have been several small studies in neonates with parenteral nutrition-associated cholestasis that have shown a beneficial effect of orally-administered UDCA in doses of 10–30 mg/kg BW per d⁽Reference Chen, Tsao, Chen, Chou, Hsieh and Chang^80–Reference Spagnuolo, Iorio, Vegnente and Guarino⁸³⁾. In this patient group UDCA has been shown to improve LFT and reduce the duration of cholestasis⁽Reference Chen, Tsao, Chen, Chou, Hsieh and Chang^80–Reference Spagnuolo, Iorio, Vegnente and Guarino⁸³⁾. This outcome is achieved despite a very short residual intestine in some neonates. However, some studies have shown rebound cholestasis on withdrawal of UDCA in children in whom enteral nutrition had not been established⁽Reference De Marco, Sordino, Bruzzese, Di Caro, Mambretti, Tramontano, Colombo, Simoni and Guarino⁸¹⁾. Evidence of a benefit of UDCA in adults is more limited, with a single study showing that treatment with an average of 11·2 mg oral UDCA/kg BW per d is associated with a reduction in γ-glutamyl transferase and alanine aminotransferase levels but not ALP, aspartate aminotransferase or bilirubin levels⁽Reference Beau, Labat-Labourdette, Ingrand and Beauchant⁸⁴⁾. UDCA may also worsen diarrhoea in some individuals⁽Reference Howard and Ashley⁸⁵⁾.

As mentioned earlier, there is evidence that levels of the S-containing amino acids choline and taurine are reduced in patients receiving parenteral nutrition⁽Reference Buchman^32, Reference Cooper, Betts, Pereira and Ziegler^44, Reference Schneider, Joly, Gehrardt, Badran, Myara, Thuillier, Coudray-Lucas, Cynober, Trivin and Messing^47, Reference Buchman, Dubin, Moukarzel, Jenden, Roch, Rice, Gornbein and Ament^86, Reference Misra, Ahn, Ament, Choi, Jenden, Roch and Buchman⁸⁷⁾. Taurine is especially low in neonates and is now often added to neonatal parenteral nutrition formulations, but not to those of adults. Multivariate analysis of data collected as part of a larger multi-centre trial investigating the management of cholestasis in neonates receiving parenteral nutrition has suggested that parenteral taurine reduces the incidence of cholestasis in severely-premature infants and those with necrotizing enterocolitis⁽Reference Spencer, Yu and Tracy⁴⁶⁾. There is considerably less evidence of a benefit of taurine supplementation in adults, with a reduction in aspartate aminotransferase levels being reported in a single small study of adults receiving long-term parenteral nutrition⁽Reference Schneider, Joly, Gehrardt, Badran, Myara, Thuillier, Coudray-Lucas, Cynober, Trivin and Messing⁴⁷⁾. Similarly, small-scale trials of choline supplementation in adults have demonstrated that both parenteral choline and high-dose oral lecithin can increase plasma choline concentrations⁽Reference Buchman, Dubin, Jenden, Moukarzel, Roch, Rice, Gornbein, Ament and Eckhert^40, Reference Buchman, Ament, Sohel, Dubin, Jenden, Roch, Pownall, Farley, Awal and Ahn^41, Reference Buchman, Dubin, Moukarzel, Jenden, Roch, Rice, Gornbein and Ament⁸⁶⁾. This outcome has been shown to be associated with a reduction in hepatic steatosis, assessed by computerised tomography scanning, and improvements in plasma ALP, alanine aminotransferase and aspartate aminotransferase concentrations⁽Reference Buchman, Ament, Sohel, Dubin, Jenden, Roch, Pownall, Farley, Awal and Ahn⁴¹⁾. Further larger trials investigating the possible beneficial effects of both choline and taurine are ongoing.

Small intestine and liver transplantation

Impending or overt liver failure associated with PNALD is recognised as an indication for small intestinal transplantation⁽Reference Buchman, Scolapio and Fryer⁷⁴⁾, and PNALD is one of the commonest reasons for performing intestinal transplantation⁽Reference Grant, Abu-Elmagd, Reyes, Tzakis, Langnas, Fishbein, Goulet and Farmer⁸⁸⁾. The definition of impending and overt liver failure includes patients with ‘elevated serum bilirubin and/or liver enzymes, splenomegaly, thrombocytopenia, gastroesophageal varices, coagulopathy, stomal bleeding or hepatic fibrosis or cirrhosis’⁽Reference Buchman, Scolapio and Fryer⁷⁴⁾. This definition is very broad and would include patients ranging from those with relatively-mild LFT abnormalities to those with ESLD. UK transplant units have suggested consideration of transplantation only if there is portal hypertension, cirrhosis or bridging fibrosis⁽Reference Middleton and Jamieson⁸⁹⁾. Survival after intestinal transplantation is not as good as after other solid organ transplants⁽Reference Grant, Abu-Elmagd, Reyes, Tzakis, Langnas, Fishbein, Goulet and Farmer⁸⁸⁾. Survival is worst for individuals undergoing combined liver and small intestine transplantation, with a 1-year survival of only 60%; 1-year survival after transplantation of small intestine alone is better at 77%⁽Reference Grant, Abu-Elmagd, Reyes, Tzakis, Langnas, Fishbein, Goulet and Farmer⁸⁸⁾. There is evidence to suggest that for individuals who do not have irreversible PNALD small intestinal transplantation alone may be a viable option because of recovery of liver dysfunction after transplantation⁽Reference Lauro, Zanfi and Ercolani²¹⁾. However, in adults with ESLD combined liver and small intestine transplantation will be required. In neonates and infants, for whom there is the possibility of an extent of intestinal adaptation and weaning from parenteral nutrition, transplantation of liver alone, which has a considerably better outcome than combined small intestine and liver transplantation, may be possible as a bridging measure until enteral nutrition is established.