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

 

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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.

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
  CrossrefPubMedGoogle Scholar
• 2 Rager R, Finegold M J. Cholestasis in immature newborn infants: is parenteral alimentation responsible?.  J Pediatr. 1975;  86 264-269
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 4 Btaiche I F, Khalidi N. Parenteral nutrition-associated liver complications in children.  Pharmacotherapy. 2002;  22 188-211
  CrossrefPubMedGoogle Scholar
• 5 Kelly D A. Liver complications of pediatric parenteral nutrition: epidemiology.  Nutrition. 1998;  14 153-157
  CrossrefPubMedGoogle Scholar
• 6 Kelly D A. Intestinal failure-associated liver disease: what do we know today?.  Gastroenterology. 2006;  130(suppl 1) S70-S77
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 8 Teitelbaum D H. Parenteral nutrition-associated cholestasis.  Curr Opin Pediatr. 1997;  9 270-275
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 17 Hadaway L C. Best-practice interventions: keeping central line infection at bay.  Nursing. 2006;  36 58-63 , quiz 63-54
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 25 Braxton C, Lowry S F. Parenteral nutrition and liver dysfunction: new insight?.  JPEN J Parenter Enteral Nutr. 1995;  19 3-4
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 28 Goulet O, Ruemmele F. Causes and management of intestinal failure in children.  Gastroenterology. 2006;  130(suppl 1) S16-S28
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 33 Alverdy J C. Effects of glutamine-supplemented diets on immunology of the gut.  JPEN J Parenter Enteral Nutr. 1990;  14(suppl) 109S-113S
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 48 Scolapio J S. Short bowel syndrome: recent clinical outcomes with growth hormone.  Gastroenterology. 2006;  130(suppl 1) S122-S126
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 51 Jeppesen P B. The use of hormonal growth factors in the treatment of patients with short-bowel syndrome.  Drugs. 2006;  66 581-589
  CrossrefPubMedGoogle Scholar
• 52 Jeppesen P B. Glucagon-like peptide-2: update of the recent clinical trials.  Gastroenterology. 2006;  130(suppl 1) S127-S131
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 54 Jeppesen P B, Mortensen P B. Experimental approaches: dietary and hormone therapy.  Best Pract Res Clin Gastroenterol. 2003;  17 1041-1054
  CrossrefPubMedGoogle Scholar
• 55 Jeppesen P B. Clinical significance of GLP-2 in short-bowel syndrome.  J Nutr. 2003;  133 3721-3724
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 57 Drucker D J. Biological actions and therapeutic potential of the glucagon-like peptides.  Gastroenterology. 2002;  122 531-544
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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); 
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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)
  PubMedGoogle Scholar
• 69 Driscoll D F. Lipid injectable emulsions: 2006.  Nutr Clin Pract. 2006;  21 381-386
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  PubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar

Beth A CarterM.D. 

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Baylor College of Medicine

6621 Fannin Street, CCC 1010.00, Houston, TX 77030