Intestinal Failure-Associated Liver Disease: Management and Treatment Strategies Past, Present, and Future

ABSTRACT

Liver disease is estimated to develop in 40% to 60% of infants on long-term parenteral nutrition (PN) secondary to intestinal failure. The etiology of intestinal failure-associated liver disease (IFALD) is multifactorial with primary contributors including prematurity, sepsis, deficiencies or hepatotoxicities of infusates, and lack of enterally stimulated bile flow. IFALD treatment strategies have historically emphasized the following: choleretics such as ursodeoxycholic acid, bowel decontamination for small bowel bacterial overgrowth, bowel tapering and lengthening procedures, and manipulations of PN prescriptions (e.g., cycling). This review highlights current and proposed novel treatment and management strategies for IFALD. These include a discussion of state-of-the art central line care practices, novel bowel-lengthening procedures such as serial transverse enteroplasty, isolated liver transplant for IFALD, probiotics and glutamine for bowel decontamination, hormonal therapies for achieving bowel adaptation, and a discussion of new PN formulations that may have emerging roles in IFALD.

KEYWORDS

Intestinal failure - total parenteral nutrition - cholestasis - liver

REFERENCES

• 1 Rhoads J E. The development of TPN: an interview with pioneer surgical nutritionist. Jonathan E, Rhoads, MD. [Interview by Carolyn T. Spencer and Charlene Compher.]  J Am Diet Assoc. 2001;  101 747-750
• 2 Rager R, Finegold M J. Cholestasis in immature newborn infants: is parenteral alimentation responsible?.  J Pediatr. 1975;  86 264-269
• 3 Beath S V, Davies P, Papadopoulou A et al.. Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk factors.  J Pediatr Surg. 1996;  31 604-606
• 4 Btaiche I F, Khalidi N. Parenteral nutrition-associated liver complications in children.  Pharmacotherapy. 2002;  22 188-211
• 5 Kelly D A. Liver complications of pediatric parenteral nutrition: epidemiology.  Nutrition. 1998;  14 153-157
• 6 Kelly D A. Intestinal failure-associated liver disease: what do we know today?.  Gastroenterology. 2006;  130(suppl 1) S70-S77
• 7 Sokol R J. Total parenteral nutrition-related liver disease.  Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1997;  38 418-428
• 8 Teitelbaum D H. Parenteral nutrition-associated cholestasis.  Curr Opin Pediatr. 1997;  9 270-275
• 9 Kurkchubasche A G, Smith S D, Rowe M I. Catheter sepsis in short-bowel syndrome.  Arch Surg. 1992;  127 21-24 discussion 24-25
• 10 Wolf A, Pohlandt F. Bacterial infection: the main cause of acute cholestasis in newborn infants receiving short-term parenteral nutrition.  J Pediatr Gastroenterol Nutr. 1989;  8 297-303
• 11 Lichtman S N, Keku J, Clark R L, Schwab J H, Sartor R B. Biliary tract disease in rats with experimental small bowel bacterial overgrowth.  Hepatology. 1991;  13 766-772
• 12 Lichtman S N, Keku J, Schwab J H, Sartor R B. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline.  Gastroenterology. 1991;  100 513-519
• 13 Lichtman S N, Sartor R B, Keku J, Schwab J H. Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth.  Gastroenterology. 1990;  98 414-423
• 14 Ghose R, Zimmerman T L, Thevananther S, Karpen S J. Endotoxin leads to rapid subcellular re-localization of hepatic RXRalpha: a novel mechanism for reduced hepatic gene expression in inflammation.  Nucl Recept. 2004;  2 4
• 15 Trauner M, Arrese M, Lee H, Boyer J L, Karpen S J. Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.  J Clin Invest. 1998;  101 2092-2100
• 16 Geier A, Fickert P, Trauner M. Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis.  Nat Clin Pract Gastroenterol Hepatol. 2006;  3 574-585
• 17 Hadaway L C. Best-practice interventions: keeping central line infection at bay.  Nursing. 2006;  36 58-63 , quiz 63-54
• 18 O'Grady N P, Alexander M, Dellinger E P et al.. Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention.  MMWR Recomm Rep. 2002;  51(RR-10) 1-29
• 19 Chaiyakunapruk N, Veenstra D L, Lipsky B A, Saint S. Chlorhexidine compared with povidone-iodine solution for vascular catheter-site care: a meta-analysis.  Ann Intern Med. 2002;  136 792-801
• 20 Dezfulian C, Lavelle J, Nallamothu B K, Kaufman S R, Saint S. Rates of infection for single-lumen versus multilumen central venous catheters: a meta-analysis.  Crit Care Med. 2003;  31 2385-2390
• 21 Bhutta A, Gilliam C, Honeycutt M et al.. Reduction of bloodstream infections associated with catheters in paediatric intensive care unit: stepwise approach.  BMJ. 2007;  334 362-365
• 22 Hanna H A, Raad I I, Hackett B et al.. Antibiotic-impregnated catheters associated with significant decrease in nosocomial and multidrug-resistant bacteremias in critically ill patients.  Chest. 2003;  124 1030-1038
• 23 Walder B, Pittet D, Tramer M R. Prevention of bloodstream infections with central venous catheters treated with anti-infective agents depends on catheter type and insertion time: evidence from a meta-analysis.  Infect Control Hosp Epidemiol. 2002;  23 748-756
• 24 Marciante K D, Veenstra D L, Lipsky B A, Saint S. Which antimicrobial impregnated central venous catheter should we use? Modeling the costs and outcomes of antimicrobial catheter use.  Am J Infect Control. 2003;  31 1-8
• 25 Braxton C, Lowry S F. Parenteral nutrition and liver dysfunction: new insight?.  JPEN J Parenter Enteral Nutr. 1995;  19 3-4
• 26 Kaufman S S, Loseke C A, Lupo J V et al.. Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with short bowel syndrome.  J Pediatr. 1997;  131 356-361
• 27 Sondheimer J M, Asturias E, Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition.  J Pediatr Gastroenterol Nutr. 1998;  27 131-137
• 28 Goulet O, Ruemmele F. Causes and management of intestinal failure in children.  Gastroenterology. 2006;  130(suppl 1) S16-S28
• 29 Spaeth G, Gottwald T, Hirner A. Fibre is an essential ingredient of enteral diets to limit bacterial translocation in rats.  Eur J Surg. 1995;  161 513-518
• 30 Spaeth G, Specian R D, Berg R D, Deitch E A. Bulk prevents bacterial translocation induced by the oral administration of total parenteral nutrition solution.  JPEN J Parenter Enteral Nutr. 1990;  14 442-447
• 31 Ding L A, Li J S. Effects of glutamine on intestinal permeability and bacterial translocation in TPN-rats with endotoxemia.  World J Gastroenterol. 2003;  9 1327-1332
• 32 Alverdy J A, Aoys E, Weiss-Carrington P, Burke D A. The effect of glutamine-enriched TPN on gut immune cellularity.  J Surg Res. 1992;  52 34-38
• 33 Alverdy J C. Effects of glutamine-supplemented diets on immunology of the gut.  JPEN J Parenter Enteral Nutr. 1990;  14(suppl) 109S-113S
• 34 Neu J, Roig J C, Meetze W H et al.. Enteral glutamine supplementation for very low birth weight infants decreases morbidity.  J Pediatr. 1997;  131 691-699
• 35 Lin M T, Kung S P, Yeh S L et al.. Glutamine-supplemented total parenteral nutrition attenuates plasma interleukin-6 in surgical patients with lower disease severity.  World J Gastroenterol. 2005;  11 6197-6201
• 36 Albers M J, Steyerberg E W, Hazebroek F W et al.. Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial.  Ann Surg. 2005;  241 599-606
• 37 Vanderhoof J A, Young R J, Murray N, Kaufman S S. Treatment strategies for small bowel bacterial overgrowth in short bowel syndrome.  J Pediatr Gastroenterol Nutr. 1998;  27 155-160
• 38 Lee S J, Cho S J, Park E A. Effects of probiotics on enteric flora and feeding tolerance in preterm infants.  Neonatology. 2007;  91 174-179
• 39 Attar A, Flourie B, Rambaud J C, Franchisseur C, Ruszniewski P, Bouhnik Y. Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea: a crossover, randomized trial.  Gastroenterology. 1999;  117 794-797
• 40 Tannuri U. Serial transverse enteroplasty (STEP): a novel bowel lengthening procedure, and serial transverse enteroplasty for short bowel syndrome.  J Pediatr Surg. 2003;  38 1845 , author reply 1845-1846
• 41 Kim H B, Lee P W, Garza J, Duggan C, Fauza D, Jaksic T. Serial transverse enteroplasty for short bowel syndrome: a case report.  J Pediatr Surg. 2003;  38 881-885
• 42 Kim H B, Fauza D, Garza J, Oh J T, Nurko S, Jaksic T. Serial transverse enteroplasty (STEP): a novel bowel lengthening procedure.  J Pediatr Surg. 2003;  38 425-429
• 43 Modi B P, Javid P J, Jaksic T et al.. First report of the international serial transverse enteroplasty data registry: indications, efficacy, and complications.  J Am Coll Surg. 2007;  204 365-371
• 44 Duggan C, Piper H, Javid P J et al.. Growth and nutritional status in infants with short-bowel syndrome after the serial transverse enteroplasty procedure.  Clin Gastroenterol Hepatol. 2006;  4 1237-1241
• 45 Javid P J, Kim H B, Duggan C P, Jaksic T. Serial transverse enteroplasty is associated with successful short-term outcomes in infants with short bowel syndrome.  J Pediatr Surg. 2005;  40 1019-1023 , discussion 1023-1014
• 46 Piper H, Modi B P, Kim H B, Fauza D, Glickman J, Jaksic T. The second STEP: the feasibility of repeat serial transverse enteroplasty.  J Pediatr Surg. 2006;  41 1951-1956
• 47 Chang R W, Javid P J, Oh J T et al.. Serial transverse enteroplasty enhances intestinal function in a model of short bowel syndrome.  Ann Surg. 2006;  243 223-228
• 48 Scolapio J S. Short bowel syndrome: recent clinical outcomes with growth hormone.  Gastroenterology. 2006;  130(suppl 1) S122-S126
• 49 Scolapio J S, Camilleri M, Fleming C R et al.. Effect of growth hormone, glutamine, and diet on adaptation in short-bowel syndrome: a randomized, controlled study.  Gastroenterology. 1997;  113 1074-1081
• 50 Seguy D, Vahedi K, Kapel N, Souberbielle J C, Messing B. Low-dose growth hormone in adult home parenteral nutrition-dependent short bowel syndrome patients: a positive study.  Gastroenterology. 2003;  124 293-302
• 51 Jeppesen P B. The use of hormonal growth factors in the treatment of patients with short-bowel syndrome.  Drugs. 2006;  66 581-589
• 52 Jeppesen P B. Glucagon-like peptide-2: update of the recent clinical trials.  Gastroenterology. 2006;  130(suppl 1) S127-S131
• 53 Jeppesen P B, Sanguinetti E L, Buchman A et al.. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients.  Gut. 2005;  54 1224-1231
• 54 Jeppesen P B, Mortensen P B. Experimental approaches: dietary and hormone therapy.  Best Pract Res Clin Gastroenterol. 2003;  17 1041-1054
• 55 Jeppesen P B. Clinical significance of GLP-2 in short-bowel syndrome.  J Nutr. 2003;  133 3721-3724
• 56 Jeppesen P B, Hartmann B, Thulesen J et al.. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon.  Gastroenterology. 2001;  120 806-815
• 57 Drucker D J. Biological actions and therapeutic potential of the glucagon-like peptides.  Gastroenterology. 2002;  122 531-544
• 58 Wojdemann M, Wettergren A, Hartmann B, Holst J J. Glucagon-like peptide-2 inhibits centrally induced antral motility in pigs.  Scand J Gastroenterol. 1998;  33 828-832
• 59 Wojdemann M, Wettergren A, Hartmann B, Hilsted L, Holst J J. Inhibition of sham feeding-stimulated human gastric acid secretion by glucagon-like peptide-2.  J Clin Endocrinol Metab. 1999;  84 2513-2517
• 60 Sangild P T, Tappenden K A, Malo C et al.. Glucagon-like peptide 2 stimulates intestinal nutrient absorption in parenterally fed newborn pigs.  J Pediatr Gastroenterol Nutr. 2006;  43 160-167
• 61 Cavicchi M, Beau P, Crenn P, Degott C, Messing B. Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure.  Ann Intern Med. 2000;  132 525-532
• 62 Colomb V, Jobert-Giraud A, Lacaille F, Goulet O, Fournet J C, Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children.  JPEN J Parenter Enteral Nutr. 2000;  24 345-350
• 63 Iyer K R, Spitz L, Clayton P. BAPS prize lecture-New insight into mechanisms of parenteral nutrition-associated cholestasis: role of plant sterols. British Association of Paediatric Surgeons.  J Pediatr Surg. 1998;  33 1-6
• 64 Clayton P T, Whitfield P, Iyer K. The role of phytosterols in the pathogenesis of liver complications of pediatric parenteral nutrition.  Nutrition. 1998;  14 158-164
• 65 Clayton P T, Bowron A, Mills K A, Massoud A, Casteels M, Milla P J. Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease.  Gastroenterology. 1993;  105 1806-1813
• 66 Carter B A, Taylor O A, Prendergast D R et al.. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor, FXR.  Pediatr Res. 2007; July 6 (Epub ahead of print); 
• 67 Carter B A, Prendergast D R, von Furstenberg R, Karpen S J. Soy-lipid derived stigmasterol suppresses FXR target genes, BSEP and FGF-19, in human hepatoblastoma cells: potential role in total parenteral nutrition-associated cholestasis (TPNAC).  Hepatology. 2005;  42 412A
• 68 Carter B A, Taylor O A, von Furstenberg R, Karpen S J. Soy lipid-derived stigmasterol (Stig) antagonizes bile acid (BA)-activation of the FXR dependent BA sinusoidal efflux pump genes, OSTα/β, in primary mouse hepatocytes and HepG2cells.  J Pediatr Gastroenterol Nutr. 2006;  43 E35 (Abstract)
• 69 Driscoll D F. Lipid injectable emulsions: 2006.  Nutr Clin Pract. 2006;  21 381-386
• 70 Gura K M, Duggan C P, Collier S B et al.. Reversal of parenteral nutrition-associated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management.  Pediatrics. 2006;  118 e197-e201
• 71 Antebi H, Mansoor O, Ferrier C et al.. Liver function and plasma antioxidant status in intensive care unit patients requiring total parenteral nutrition: comparison of 2 fat emulsions.  JPEN J Parenter Enteral Nutr. 2004;  28 142-148
• 72 Mertes N, Grimm H, Furst P, Stehle P. Safety and efficacy of a new parenteral lipid emulsion (SMOFlipid) in surgical patients: a randomized, double-blind, multicenter study.  Ann Nutr Metab. 2006;  50 253-259
• 73 Horslen S P, Sudan D L, Iyer K R et al.. Isolated liver transplantation in infants with end-stage liver disease associated with short bowel syndrome.  Ann Surg. 2002;  235 435-439
• 74 Muiesan P, Dhawan A, Novelli M, Mieli-Vergani G, Rela M, Heaton N D. Isolated liver transplant and sequential small bowel transplantation for intestinal failure and related liver disease in children.  Transplantation. 2000;  69 2323-2326
• 75 Weber T R, Keller M S. Adverse effects of liver dysfunction and portal hypertension on intestinal adaptation in short bowel syndrome in children.  Am J Surg. 2002;  184 582-586 , discussion 586
• 76 Botha J F, Grant W J, Torres C et al.. Isolated liver transplantation in infants with end-stage liver disease due to short bowel syndrome.  Liver Transpl. 2006;  12 1062-1066