|LETTER TO THE EDITOR
|Year : 2013 | Volume
| Issue : 2 | Page : 113-114
Throwing light on parenteral nutrition- associated liver disease
Department of Internal Medicine, Princess Durru Shehvar Children's and General Hospital, Hyderabad, India
|Date of Web Publication||6-Jul-2013|
Department of Internal Medicine, Princess Durru Shehvar Children's and General Hospital, Hyderabad
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Gude D. Throwing light on parenteral nutrition- associated liver disease. J Med Nutr Nutraceut 2013;2:113-4
Total parenteral nutrition (TPN), although essential for patients with impaired gut function, may lead to parenteral nutrition-associated liver disease (PNALD). The incidence of PNALD varies from being 40% to 60% of infants to 15-40% among adults.  PNALD is a major cause of morbidity, liver transplantation, and death in patients on TPN especially with predisposing factors such as prior liver dysfunction, prematurity and/or low birth weight, short bowel syndrome, sepsis, lack of enteral nutrition, longer duration of TPN, maximum caloric and carbohydrate intake, etc. 
Immature liver function (as evidenced from increased incidence in prematurity, low birth weight, and intrauterine growth restriction) is known to predispose to PNALD as the nascent liver is more sensitive to the pathogenic factors. In short bowel syndrome, an exaggerated pro-inflammatory cytokine response, increased bacterial translocation and sepsis, altered gut hormone secretion and bile flow coupled with deficiency of nutrients such as essential fatty acids, carnitine, choline, taurine, vitamin E, and selenium are known to play major roles in causing PNALD. The risk is further compounded by greater resection of bowel and longer duration of TPN. Inflammatory mediators in sepsis are likely the culprits in worsening PNALD. Deficiency of taurine and/or L-cysteine, L-glutamine, choline, carnitine, and excess methionine (and/or excessive carbohydrates) are also known to exacerbate PNALD. Factors such aschemical composition of the tubing used to infuse PN, toxicity from trace elements, and aluminum toxicity may also contribute to PNALD.
TPN may disrupt the normal enterohepatic circulation of bile acids. The clinical spectrum includes ductopenia, hepatic steatosis, steatohepatitis, cholestasis, cholelithiasis and its complications, hepatic fibrosis (portal and perivenular), and acalculous cholecystitis.  Progression to biliary cirrhosis and the development of portal hypertension and liver failure may occur in some cases. The duration of TPN, short bowel syndrome requiring multiple laparotomies, and recurrent sepsis may compound the risk of PNALD. The lack of enteral feeding translates into reduced gut hormone secretion, reduced bile flow and biliary stasis which leads to the development of cholestasis, biliary sludge, and gallstones which may further deteriorate the liver dysfunction.  Patients on exclusively parenteral nutrition are three times more likely to have liver dysfunction apart from perturbations in potassium, creatinine, glucose, gamma-glutamyl transferase, alkaline phosphatase levels, and liver triglycerides. Hepatic dysfunction from parenteral nutrition (PN) is known to be associated with increased length of hospital stay and mortality.  Markers of liver injury (e.g., elevated liver enzymes) may not predict the degree of hepatocellular injury or fibrosis. In severe and refractory cases, serial liver biopsies may help us gauge the degree of PNALD.
Decreased circulating metabolic hormone, fibroblast growth factor-19, has been shown to contribute to PNALD.  Deficiency in autophagy (a pathway to clear damaged organelles and large ubiquitinated proteins and aggregates) maybe another mechanism through which parenteral nutrition elicits the hepatic abnormalities. The amount of infused amino acids in critically ill patients correlated with the severity of autophagy deficiency. The resultant PNALD from TPN in the model showed fewer autophagosomes, fewer intact mitochondria, suppressed respiratory chain activity, and an increase in markers of liver damage.  An animal model observed that lipopolysaccharide, Toll-like receptor-4 signaling dependent Kupffer cell activation, may act as an early event in the pathogenesis of PNALD. 
In infants with necrotizing enterocolitis (NEC), the severity of NEC, including the need for small-bowel resection or proximal jejunostomy, as well as longer exposure to parenteral nutrition may amplify PNALD. Identification of these and other risk factors may help prevent and better manage PNALD.  It is noted that the incident significant hepatic fibrosis and liver dysfunction in PNALD may regress with isolated intestinal transplantation without the need for concurrent liver transplantation and its associated higher morbidity and mortality.  Given the degree of morbidity associated with procedures such as transplantation, they may be considered on a case-by-case basis balancing the risk-benefit ratio.
Supplementation with omega-3 polyunsaturated fatty acids normalizes the raised bilirubin values and improves fatty acid profile and liver histology. Enteral chenodeoxycholic acid demonstrates resolution in PNALD and acts as a potent intestinal trophic agent and secretagogue for Glucagon like peptide (GLP)-2.  In a study, use of intravenous fat-emulsion reduction to 1 g/kg/day 2 times per week in neonates diagnosed with PNALD resulted in a significant decline in total bilirubin levels and improved live function.  Infliximab (anti-TNF-αmonoclonal antibody) has been shown to ameliorate the progression of PNALD. It betters the pathological score and serum alanine aminotransferase, total bilirubin, and direct bilirubin levels and improves the expression of hepatic ABC transporter genes. 
Apart from the above modalities, considering early enteral feeding, a multidisciplinary approach, to the management of parenteral nutrition with prophylactic cholecystectomy, cholecystokinin infusion, aseptic catheter techniques to reduce sepsis, use of soy bean/medium chain triglyceride/olive oil/fish oil, cyclical TPN, and oral ursodeoxycholic acid may be of benefit in PNALD.
| Acknowledgments|| |
We thank our colleagues and staff of the Department of Internal Medicine for their perpetual support.
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