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Parenteral Nutrition–Associated Conjugated Hyperbilirubinemia in Hospitalized Infants

https://doi.org/10.1016/j.jada.2010.08.012Get rights and content

Abstract

Parenteral nutrition-associated conjugated hyperbilirubinemia (PNAC), commonly defined as direct bilirubin ≥2 mg/dL (34.2 μmol/L), is primarily a pediatric disease with premature infants being the most susceptible. Severe morbidity and increased mortality are associated with bilirubin >10 mg/dL (171.0 μmol/L). The lack of knowledge regarding the cause of PNAC has stymied development of prevention and treatment strategies. A systematic search of published reports was conducted to provide data on histopathology of PNAC and to review prospective, randomized, controlled trials in hospitalized infants. In experiments of young animals, parenteral nutrition (PN) with and without soy oil emulsion is directly linked to hyperbilirubinemia, and the effects are exaggerated by overfeeding. In infants, the most consistently reported risk factor for PNAC is the duration of PN. The only known effective modality is the transition to full enteral feeding and discontinuation of PN. Emerging clinical research is evaluating the role of lipid source (soy vs fish) and motility agents, such as erythromycin. Different trace element preparations are associated with varying severity of cholestasis, a finding that also deserves more study. This article reviews the prevalence, risk factors, clinical presentation, and treatment options for PNAC in neonatal intensive care units.

Section snippets

Search Strategies

Published reports were identified by searching the PubMed electronic database, limited to the English language. Searches were conducted for specific relevant text words as listed in Figure 1. A description of the molecular mechanisms regulating expression of transport systems and enzymes that may be contributing to PNAC or are hepatoprotective is beyond the scope of this review, but is available elsewhere (4, 5).

Study Selection

Eligible studies were included for review if they provided observational data in

Summary of Preclinical Evidence of Etiology

Animal experiments demonstrate that PN solutions themselves, whether fed orally or parenterally, are associated with liver injury, and that gut disuse exacerbates the problem. Both fat-free PN and mixed-fuel (ie, soy oil emulsion-containing) PN are linked to elevated serum total bilirubin in controlled experiments, and the effect is exaggerated by overfeeding. The protective effects of fish oil should be further investigated.

Diagnosis

Conjugated hyperbilirubinemia, a hallmark of PNAC, can be caused by several mechanisms that interrupt normal metabolism, transport and excretion of bilirubin (Figure 5) (5, 59, 60). Hence, PNAC remains a diagnosis of exclusion. Assessment begins with review of the clinical history, a physical examination, and generation of a differential diagnosis. The differentiation of PNAC from obstructive causes of cholestasis (eg, extrahepatic biliary atresia), primary liver disease and metabolic liver

Prevention and Treatment

The only known effective modality for PNAC is to transition to full enteral feeding and discontinue PN, which, unfortunately, is not an option for many infants. Preventative and alternative life-sustaining treatment strategies would dramatically improve clinical practice. The best care at this time is to provide optimal nourishment without overfeeding and minimize exposure to PN-contaminants and to medications that can injure the liver.

Rehabilitation and Surgical Management

Ideally, all infants who are expected to be on prolonged PN would be in an intestinal rehabilitation program (84). If disease progresses, intestinal transplant options might be considered. Kaufman and colleagues (85) suggest that for intractable cases associated with Stage 3 or 4 fibrosis, which are often not reversible, early referral of patients for intestinal and/or liver transplantation is especially important to increase chances for long-term survival (85).

Clinical Prevention Trials

Prospective, randomized controlled trials have been undertaken to test the prophylactic effects of the drugs CCK erythromycin, and ursodeoxycholic acid on PNAC. Controlled studies also explored the role of protein load, individual amino acids, trace elements, and hypocaloric enteral feeding on incidence of PNAC.

Conclusions

Despite 40 years of clinical experience with PN, the cause of PNAC remains unknown and its link to nutrition support is especially puzzling. Potential causes include PN-contaminants, nutrient excess or deficiency, gut atrophy, and sepsis-related factors. In addition, the composition and/or source of macronutrients may play a role.

The histology and pathology of pediatric PNAC is unique and is not seen in adults. Clinicians can consider that infants having prematurity, congenital enteropathies,

C. J. Klein is director, Bionutrition Research Program, Children's National Medical Center and an assistant research professor, Department of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC.

References (110)

  • G.F. Whalen et al.

    A proposed cause for the hepatic dysfunction associated with parenteral nutrition

    J Pediatr Surg.

    (1990)
  • M. Oshita et al.

    Significance of administration of fat emulsion: Hepatic changes in infant rats receiving total parenteral nutrition with and without fat

    Clin Nutr.

    (2004)
  • S. Hata et al.

    Effect of amino acids in total parenteral nutrition on cholestasis in newborn rabbits

    J Pediatr Surg.

    (1994)
  • T.P. Stein et al.

    Protein and fat metabolism in rats during repletion with total parenteral nutrition (TPN)

    J Nutr.

    (1981)
  • S. Loff et al.

    Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers

    J Pediatr Surg.

    (2000)
  • P.T. Clayton et al.

    Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease

    Gastroenterology

    (1993)
  • K.R. Iyer et al.

    BAPS prize lecture: New insight into mechanisms of parenteral nutrition-associated cholestasis: Role of plant sterols

    J Pediatr Surg.

    (1998)
  • M. Demircan et al.

    Determination of serum bile acids routinely may prevent delay in diagnosis of total parenteral nutrition-induced cholestasis

    J Pediatr Surg.

    (1999)
  • W.F. Balistreri et al.

    Pathologic versus physiologic cholestasis: Elevated serum concentration of a secondary bile acid in the presence of hepatobiliary disease

    J Pediatr.

    (1981)
  • A. Cooper et al.

    Resolution of intractable cholestasis associated with total parenteral nutrition following biliary irrigation

    J Pediatr Surg.

    (1985)
  • C.J. Klein et al.

    Overfeeding macronutrients to critically ill adults: Metabolic complications

    J Am Diet Assoc.

    (1998)
  • D.A. Kelly

    Intestinal failure-associated liver disease: What do we know today?

    Gastroenterology

    (2006)
  • S.S. Kaufman et al.

    Parenteral nutrition associated liver disease

    Semin Neonatol.

    (2003)
  • P.C. Ng et al.

    High-dose oral erythromycin decreased the incidence of parenteral nutrition-associated cholestasis in preterm infants

    Gastroenterology

    (2007)
  • C. Duggan et al.

    Glutamine supplementation in infants with gastrointestinal disease: A randomized, placebo-controlled pilot trial

    Nutrition

    (2004)
  • A. Cooper et al.

    Taurine deficiency in the severe hepatic dysfunction complicating total parenteral nutrition

    J Pediatr Surg.

    (1984)
  • T.A. Slagle et al.

    Effect of early low-volume enteral substrate on subsequent feeding tolerance in very low birth weight infants

    J Pediatr.

    (1988)
  • D.W. Wilmore et al.

    Growth and development of an infant receiving all nutrients exclusively by vein

    JAMA

    (1968)
  • J.L. Rombeau et al.

    Quaker Sense and Sensibility in the World of Surgery

    (1997)
  • B.A. Carter et al.

    Mechanisms of disease: update on the molecular etiology and fundamentals of parenteral nutrition associated cholestasis

    Nat Clin Pract Gastroenterol Hepatol.

    (2007)
  • C.M. Healy et al.

    Fluconazole prophylaxis in extremely low birth weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole-resistant Candida species

    Pediatrics

    (2008)
  • K. Wright et al.

    Increased incidence of parenteral nutrition-associated cholestasis with aminosyn PF compared to trophamine

    J Perinatol.

    (2003)
  • J. Koglmeier et al.

    Clinical outcome in patients from a single region who were dependent on parenteral nutrition for 28 days or more

    Arch Dis Child

    (2008)
  • R.D. Christensen et al.

    Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease

    J Perinatol.

    (2007)
  • M. Steinbach et al.

    Demographic and nutritional factors associated with prolonged cholestatic jaundice in the premature infant

    J Perinatol.

    (2008)
  • A.U. Spencer et al.

    Parenteral nutrition-associated cholestasis in neonates: Multivariate analysis of the potential protective effect of taurine

    JPEN J Parenter Enteral Nutr.

    (2005)
  • V. Hoang et al.

    Percutaneously inserted central catheter for total parenteral nutrition in neonates: Complications rates related to upper versus lower extremity insertion

    Pediatrics

    (2008)
  • H. von Rettberg et al.

    Use of di(2-ethylhexyl)phthalate-containing infusion systems increases the risk for cholestasis

    Pediatrics

    (2009)
  • E. Zambrano et al.

    Total parenteral nutrition induced liver pathology: An autopsy series of 24 newborn cases

    Pediatr Dev Pathol.

    (2004)
  • T.C. Willis et al.

    High rates of mortality and morbidity occur in infants with parenteral nutrition-associated cholestasis

    JPEN J Parenter Enteral Nutr.

    (2010)
  • D. Sigalet et al.

    Improved outcomes in paediatric intestinal failure with aggressive prevention of liver disease

    Eur J Pediatr Surg.

    (2009)
  • K.M. Gura et al.

    Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease

    Pediatrics

    (2008)
  • J.F. Watchko

    Identification of neonates at risk for hazardous hyperbilirubinemia: Emerging clinical insights

    Pediatr Clin North Am.

    (2009)
  • L. Vitek et al.

    Enterohepatic cycling of bilirubin as a cause of ‘black' pigment gallstones in adult life

    Eur J Clin Invest.

    (2003)
  • D. Zovko et al.

    Long-term total parenteral nutrition and cholecystostomy tube in a rabbit model surgical procedure: Management and preliminary results

    Res Exp Med (Berlin)

    (1996)
  • D.R. Duerksen et al.

    Total parenteral nutrition impairs bile flow and alters bile composition in newborn piglet

    Dig Dis Sci.

    (1996)
  • S. Loff et al.

    Parenteral nutrition-induced hepatobiliary dysfunction in infants and prepubertal rabbits

    Pediatr Surg Int.

    (1999)
  • B. Waters et al.

    Effect of route of nutrition on recovery of hepatic organic anion clearance after fasting

    Surgery

    (1994)
  • J.B. Das et al.

    Biliary lipid composition and bile acid profiles during and after enteral fast of total parenteral nutrition in the rabbit

    J Pediatr Gastroenterol Nutr.

    (1996)
  • R.L. Moss et al.

    Hepatobiliary dysfunction during total parenteral nutrition is caused by infusate, not the route of administration

    J Pediatr Surg.

    (1993)

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    C. J. Klein is director, Bionutrition Research Program, Children's National Medical Center and an assistant research professor, Department of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC.

    M. Revenis is an attending neonatologist, Children's National Medical Center Division of Neonatology, and assistant professor of pediatrics, Department of Pediatrics, School of Medicine and Health Sciences, George Washington University, Washington, DC.

    C. Kusenda is clinical nutrition manager, Children's National Medical Center, Washington, DC.

    L. Scavo is an attending neotatologist, Children's National Medical Center Division of Neotatology, and an associate professor of child health and human development, School of Medicine and Health Sciences, Department of Pediatrics, George Washington University, Washington, DC.

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