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Parenteral Nutrition, Liver Disease, and N-acetyl Cysteine in Infants and Children
Diane Mager, PhD, RD
Editor’s note: There are many people working on the issue of liver complications associated with parenteral nutrition, particularly in children. This article discusses one approach that is experimental, but that appears to offer benefit.
Severe bowel dysfunction can be treated with parenteral nutrition (PN). However, one of the serious complications of this therapy is parenteral nutrition associated liver disease (PNALD). This is more common in children than adults. Estimates of mortality from liver failure are highly dependent on the group of children studied. In France, in a large cohort of children on homePN for digestive diseases (230 children), ages 0.8 to 16 years, the mortality from liver failure was 2 percent.1 In a more vulnerable population of children, in a neonatal intensive care unit in Canada, the mortality from liver failure was 37.5 percent.2
PNALD typically results in changes in liver function that range from mild to moderate changes in liver biochemistries and fatty infiltrate of the liver to inflammation, fibrosis, and cirrhosis with or without pronounced jaundice. In some patients (particularly young infants), disease progression can be rapid, with cirrhosis developing within a few months.1,3 This can result in end-stage liver failure, necessitating short bowel transplantation, with or without liver transplantation.
The current article will address some of the factors provoking PNALD in infants and children, with an emphasis on how changes in nutritional composition of PN (the amino acid composition) may alleviate this condition. Specifically we will describe how the use of N-acetyl cysteine (Mucomyst®) provided novel therapy in the treatment of PNALD in three long-term PN children.
Causes of PNALD
PNALD is thought to be caused by a variety of factors. A major cause appears to be catheter-related bloodstream infections, but the lack of enteral stimulation and the nutrition composition of PN solutions are also thought to be important contributors.
Catheter-related bloodstream infections lead to bacterial growth and proliferation, which in turn leads to bacterial production of endotoxins and oxidative damage within the liver. The use of sterile techniques can reduce the risk of catheter-related bloodstream infections, thereby protecting the liver.
Stimulation of the gastrointestinal (GI) tract by nutrients present in food is necessary to ensure that cells in the gut maintain their health and function. Lack of enteral stimulation in the gut results in an increased risk for bacterial overgrowth within the GI tract.3 Bacterial overgrowth in the proximal gut can interfere with the digestion process and gut motility, leading to nutrient malabsorption and other difficulties with weaning from PN. The introduction of food in the gut can reduce abnormal bacterial overgrowth within the upper GI tract. In children dependent on PN, however, the introduction of food should only be done when the physician deems it safe.
At present, it is not completely understood how the nutrient composition of PN solutions may contribute to an increased risk for PNALD in infants and children. This is central to our discussion, however, and will be considered in more detail in the following sections.
Nutritional Issues and PNALD
While there is no one single nutritional treatment for PNALD, typically the goal is to encourage food intake by mouth, or if this is not tolerated, through an enteral tube, in an effort to wean children off PN or at least minimize the amount of PN used to meet nutritional requirements for growth. These efforts ensure that the toxic effects of PN are minimized and that luminal nutrients stimulate gut cell growth and motility, which in turn reduces bacterial overgrowth.
It is known that it is important NOT to provide an excess of energy (calories) in the PN as this may lead to metabolic and hormonal changes that stress the liver and contribute to an increased risk for PNALD.3 However, it is essential to avoid feeding suboptimal amounts of nutrition to the child dependent on PN. Like excessive feeding, nutritional deficiency can contribute to an increased risk for liver disease in children and adults dependent upon PN. Hence, it is important to provide the right balance of nutrients to avoid the development of PNALD and to promote growth and development in infants and children.
Nutritional Composition of PN
There is some evidence that the amino acid composition of PN solutions might contribute to the toxic damage to the liver (hepatotoxicity) by PN solutions. Of particular concern are the sulfur-containing amino acids: methionine (MET), S-adenosyl methionine (SAM), and cysteine (CYS). Figure 1 shows how these amino acids are interconnected and how CYS is a precursor for the main intracellular (cytosolic) antioxidant glutathione. Glutathione, in turn, appears to stabilize the enzymes responsible for the METg SAMg CYS conversion.
PN solutions contain little or no CYS because it is highly insoluble, and no SAM because it is not commercially available. The PN solution contains as much MET as can be safely added. At high levels MET is toxic to the nervous system.
PNALD appears to coincide with disruption of these transsulfuration pathways.7 Low glutathione levels block the METg SAMg CYS conversion and this becomes a vicious cycle, since low CYS reduces the production of glutathione. When the cells’ antioxidant capacity dwindles, many cellular functions fail, such as the liver’s excretion of bile.
Our approach was to find a way to deliver CYS to patients with PNALD, in a soluble form.
Nutritional Treatment of PNALD: The Sulfur Amino Acid Perspective
We have recently studied the addition of N-acetyl cysteine (NAC) into the IV regimen of three children with PNALD.5
NAC supplementation resulted in significant improvements in liver function tests in these children. NAC is a compound that is very similar in biochemical structure (biological availability and function) to CYS.4,6,9 It is also soluble in PN solutions, which makes it easy to add to PN. NAC has been around for a long time. It is approved by the Food and Drug Administration (FDA) for treatment of acute liver failure in both adults and children.11 It has been particularly useful in the treatment of liver toxicity due to acetaminophen (Tylenol®) overdose. NAC is a powerful antioxidant. The safety of NAC has been well documented in the literature. It may only be used under the direct supervision of a physician.
Although research is limited in regard to the direct impact of NAC on liver function in humans, there is evidence that supplementation in children results in up-regulation of red blood cell glutathione synthesis.8,10 This certainly appeared to be the case in the one child who had red blood cell glutathione measured in our case series. Whether or not this was the reason why all three children experienced improvements in their liver function tests needs further study.
The preferred route of administration of NAC is intravenously, due to the higher bioavailability of NAC to liver tissues when delivered by IV. Delivery of NAC enterally is possible, but the slower gut absorption of NAC and increased utilization of NAC within the gut may mean that less NAC is available to promote liver glutathione synthesis.11 NAC is compatible with a variety of IV hydration solutions and can be run simultaneously with PN in a variety of IV solutions (e.g., IV dextrose).3 Consultation with the nutrition support pharmacist will assist caregivers in determining the best method of NAC delivery.
The key approach to treatment of PNALD is to minimize the risk of infection and to avoid over/underfeeding of PN in the child or infant dependent on long-term PN. This requires the intervention of a multidisciplinary team that works closely with the child and family.
The addition of IV NAC (at lower doses than those used for treatment of acute liver failure) to infants and children with documented PNALD was associated with improvements in red blood cell glutathione content and reductions in serum ferritin and liver biochemistries.5 This suggests that NAC supplementation could be helpful in the treatment of PNALD. Of course, this does not eliminate the need to pursue, evaluate, and implement other approaches.
The preliminary work of the case series described suggests, but does not prove, that NAC might be a helpful supportive therapy in PNALD in children and infants dependent on long-term PN. Clearly, more work needs to be done to examine the efficacy of NAC supplementation in children with PNALD.
1. Colomb V, Dabbas-Tyan M, Taupin P, Talbotec C, Revillon Y, Jan D, et al. Long-term outcome of children receiving home parenteral nutrition: A 20-year single center experience in 302 patients. Journal of pediatric gastroenterology and nutrition. 2007 Mar;44(3):347–53.
2. Wales P, de Silva N, Kim J, Lecce L, To T, Moore A. Neonatal short bowel syndrome: Population-based estimates of incidence and mortality rates. Journal of pediatric gastroenterology and nutrition. 2004 May;39(5):690–95.
3. Guglielmi FW, Regano N, Mazzuoli S, Fregnan S, Leogrande G, Guglielmi A, et al. Cholestasis induced by total parenteral nutrition. Clinics in liver disease. 2008 Feb;12(1):97–110, viii.
4. Brunton JA, Ball RO, Pencharz PB. Current total parenteral nutrition solutions for the neonate are inadequate. Current opinion in clinical nutrition and metabolic care. 2000 Jul;3(4):299–304.
5. Mager DR, Marcon M, Wales P, Pencharz PB. Use of N-acetyl cysteine for the treatment of parenteral nutrition-induced liver disease in children receiving home parenteral nutrition. Journal of pediatric gastroenterology and nutrition. 2008 Feb;46(2):220–3.
6. Shoveller AK, Brunton JA, Brand O, Pencharz PB, Ball RO. N-acetyl cysteine is a highly available precursor for cysteine in the neonatal piglet receiving parenteral nutrition. Journal of Parenteral and Enteral Nutrition. 2006 Mar-Apr;30(2):133–42.
7. Look MP, Riezler R, Reichel C, Brensing KA, Rockstroh JK, Stabler SP, et al. Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma-cystathionase? Scandinavian journal of gastroenterology. 2000 Aug;35(8):866–72.
8. Hong L, Wu J, Cai W. Glutathione decreased parenteral nutrition-induced hepatocyte injury in infant rabbits. Journal of Parenteral and Enteral Nutrition. 2007 May-Jun;31(3):199–204.
9. Shoveller AK, Brunton JA, House JD, Pencharz PB, Ball RO. Dietary cysteine reduces the methionine requirement by an equal proportion in both parenterally and enterally fed piglets. The journal of nutrition. 2003 Dec;133(12):4215–24.
10. Badaloo A, Reid M. Forrester T, Heird WC, Jahoor F. Cysteine supplementation improves the erythrocyte glutathione synthesis rate in children with severe edematous malnutrition. American Journal of Clinical Nutrition. 2002: 76(3):646–52.
11. Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transplantation. 2008 Jan;14(1):25–30.
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