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Parenteral Nutrition associated Liver dysfunction

How common is parenteral nutrition associated liver dysfunction (PNALD)?

Intestinal failure–associated liver disease develops in 15% to 40% of adults on home parenteral nutrition. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority but is more common in infants and neonates than in adults.

What is the pattern of LFTs in PNALD?

Markers of liver dysfunction include GGT, AP, ALT and AST. An elevated level of bilirubin is less common.

Is PNALD reversible?

Abnormalities of LFT in patients receiving short term PN are usually transient, but in individuals receiving long-term parenteral nutrition substantial liver damage and ultimately ESLD may occur.

What is the aetiology of parenteral nutrition-associated liver disease?

  • Patient dependent factors-
    • Underlying disease- Abnormal LFTs may be related to underlying liver disease (PSC in IBD, previous fatty liver) rather than the effects of the parenteral nutrition itself, although the effects of the latter may exacerbate the former.
    • Sepsis- major precipitating factor for abnormal LFTs
    • Intestinal anatomy- there is an increased risk of chronic cholestasis in adults with a small intestinal length of less than 50cms. This may be due to impairment of enterohepatic bile salt circulation and abnormal bile acid metabolism. Others have argued that bowel length may simply be a surrogate marker of parenteral energy requirement.
    • Bacterial overgrowth- relatively common due to intestinal stasis. This may cause liver dysfunction due to 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.
    • Lack of enteral nutrition- this causes reduced secretion of GI hormones causing reduced intestinal motility, promoting bacterial overgrowth, and may predispose to biliary stasis. Lack of enteral food also causes mucosal atrophy, which in turn allows increased bacterial translocation across the gut mucosal barrier.
  • Parenteral nutrient deficiency
    • Essential fatty acid deficiency- may cause liver dysfunction, although unlikely unless fat free parenteral regimes are used
    • 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. Carnitine, choline and taurine are not routinely administered as part of parenteral formulations.
  • Nutrient toxicity
    • Glucose infusion at rates of >5 mg/body weight (BW) per min have been demonstrated to result in steatosis in human subjects. Excess glucose infusion causes hyperinsulinemia, which then enhances glucose conversion to fat within the liver. 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 or more each day without parenteral glucose infusion has been shown to lower insulin levels and improve LFT.
    • Lipid emulsions- parenteral intake of soyabean-based lipid emulsion of
    • >1 g/kg BW per d has been shown to be associated with an increased risk of liver disease. This may be due to lipid overloading of hepatic macrophages might impair phospholipid excretion into bile and cause intrahepatic cholestasis
    • Aluminium- Al has been shown to cause cholestasis in animal models but is not found in modern parenteral formulations in substantial quantities
    • Manganese- withdrawal of parenteral Mn improves hepatic function in children with high plasma level.

How do you manage parenteral nutrition-associated liver disease?

  • Manage non-nutritional causes
    • Avoid and treat sepsis
    • Treat extrahepatic biliary obstruction- Cholelithiasis in patients receiving PN can be prevented by encouraging enteral feeding and administration of cholecystokinin or prophylactic cholecystectomy
    • Avoid hepatotoxic medications
    • Treat bacterial overgrowth- maneuvers to reduce bacterial translocation such as increased dietary fibre intake and parenteral glutamine supplementation, have not been shown to have a beneficial effect on liver dysfunction
    • Treat underlying liver disease
  • Modify enteral and parenteral nutrition
    • Avoid overfeeding- UK guidelines suggest a total daily energy intake of
    • 25–35 kcal/kg BW and a daily protein intake of 0.8–1.5 g/kg BW. The total daily calories from dextrose should be limited to 65% or less. Glucose oxidation reaches the maximal level at 4gm/kg/day). Exceeding this limit may cause lipogenesis, hypercapnia and hyperglycemia  and increased incidence of liver dysfunction.
    • Maximise enteral nutrition
    • Optimise parenteral lipid- 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. However, experimental data suggest that the intake of soyabean-based lipid should be <1.0 g/kg BW per d. There is growing evidence that lipid emulsions containing a mixture of long-chain and medium-chain triacylgylcerol (TAG) emulsions with a high MUFA content and emulsions containing fish oils 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. At the onset of liver dysfunction, consider reducing or suspending lipids such as limiting lipid infusions to 5 per week.
    • Cyclical parenteral nutrition- cyclical rather than continuous PN should be administered to minimise the adverse effects of prolonged insulin hypersecretion. Allowing an 8 h break from PN has been shown to improve LFT and reduce insulin levels. When prolonged PN therapy is expected, cycling should be started as soon as possible.
  • Pharmacological treatment
    • UDCA- Evidence of a benefit of UDCA in adults is limited. UDCA (15-20mg/kg/day) may be associated with an improvement in cholestatic LFTs. is UDCA is commonly prescribed although there is no clear evidence of efficacy. UDCA may also worsen diarrhoea in some individuals.
    • Taurine and choline- evidence supporting the widespread use of parenteral choline and taurine supplementation in the prevention or treatment of liver dysfunction remains limited.
  • Small intestinal and/or liver transplantation
    • Impending or overt liver failure associated with PNALD is recognised as an indication for small intestinal transplantation, and PNALD is one of the commonest reasons for performing intestinal transplantation.   UK transplant units have suggested consideration of transplantation only if there is portal hypertension, cirrhosis or bridging fibrosis.

Ref-

  1. Lloyd DA, Gabe SM. Managing liver dysfunction in parenteral nutrition. Proc Nutr Soc. 2007 Nov; 66(4):530-8.



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