Serum Vitamin C (mg/dl) by Salad Intake

1. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Catherine J. Klein, PhD, RD: Children's National Medical Center (CNMC) Mary Revenis, M.D.: CNMC Carolyn Kusenda, M.S., R.D.: CNMC Louis Scavo, M.D.: CNMC JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

2. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Background • Parenteral nutrition-associated conjugated hyperbilirubinemia (PNAC) is: • Primarily a pediatric disease with premature infants being the most susceptible. Infants having congenital enteropathies, necrotizing enterocolitis, and surgical short bowel syndrome are at increased risk. • Commonly defined as direct bilirubin ≥2 mg/dL. Severe morbidity and increased mortality are associated with bilirubin >10 mg/dL. • The most consistently reported risk factor associated with development of PNAC is the duration of parenteral nutrition (PN). The lack of knowledge regarding the cause of PNAC has stymied prevention and treatment strategies. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

3. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Etiology • A model of normal bilirubin metabolism, circulation, sequestration and excretion is presented in the figure. Despite 40 years of clinical experience with PN, the cause of PNAC remains unknown. Its link to PN is puzzling. • Animal experiments demonstrate that PN-solutions themselves, whether fed orally or parenterally, are associated with liver injury. • Both fat-free PN and mixed-fuel (soy oil-emulsion containing) PN are linked to elevated serum total bilirubin in controlled experiments. In animals, overfeeding worsens elevated serum total bilirubin. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

4. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Etiology (cont’d) • Thus, PNAC is thought to occur from: • PN route and formula, which instigate histological damage in the liver, resulting in impaired hepatic bile flow (cholestasis). • Bowel disuse, gut-atrophy and an adynamic gallbladder (cholestasis). • Upsurge in release of conjugated bilirubin as the uridine diphosphate glucuronosyltransferase 1A1 liver enzyme (UDPGT) becomes more functional in conjugating bilirubin 4-8 weeks after birth. • Disease processes, sepsis-related factors and medications that impact the liver. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

5. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants RBC Heme Biliverdin CB CB CB CB CB CB CB CB CB CB CB CB CB CB CB UB UB UB UB UB Albumin Albumin Bile Bile Bile UBG UBG UBG UBG UN UN Secretin Secretin CCK CCK SB SB Fecal Excretion RES Model of bilirubin metabolism, circulation, sequestration and excretion GA Liver UDPGT Spleen Common Bile Duct Kidneys Gallbladder Blood Colonic Bacteria Urinary excretion Intestines Passive absorption Unconjugated bilirubin released from the degradation of heme is taken up by the liver where it is conjugated and secreted in bile to facilitate the absorption of fat during digestion. Bilirubin and its derivatives are excreted in feces and urine. CB: conjugated bilirubin; CCK: cholecystokinin; GA: glucuronic acid; RES: reticuloendothelial system; RBC: red blood cell; SB: stercobiligen; UB: unconjugated bilirubin; UBG: urobilinogin; UDPGT: uridine diphosphate glucuronosyltransferase enzyme; UN: urobilin. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

6. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Clinical Prevention Trials • Trials that showed potential effectiveness included: • Lower amounts of manganese, iron, and iodine in combination with higher amounts of zinc and selenium. • Amino acid-free parenteral nutrition and enteral protein, for those who can tolerate some enteral feeding. • Erythromycin, perhaps as a pro-kinetic agent. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

7. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Clinical Prevention Trials (cont’d) • Trials that failed to demonstrate effectiveness included: • Change in dose of parenteral amino acids. • Early hypocaloric enteral feeding. • Enteral glutamine supplementation. • Greater amounts of parenteral macronutrients and more aggressive attempts to establish and advance enteral feeding. • Cholecystokinin-octapeptide,tauroursodeoxycholic acid, ursodeoxycholic acid. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

8. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Clinical Prevention Trials (cont’d) • Concepts that deserve further clinical investigation include: • Replacement of soy oil-emulsion with fish oil-emulsion. • Use of prebiotics, vitamin E, anti-inflammatory medications, and prokinetic agents, such as erythromycin. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

9. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Clinical Considerations • Registered dietitians who specialize in neonatal nutrition support are uniquely qualified to assist the medical team in minimizing risk factors related to PN and in advancing enteral feedings to facilitate the discontinuation of PN. • Provide optimal nourishment without overfeeding. • Minimize exposure to medications that can injure the liver and to PN-contaminants (use plasticizer-free infusion sets; protect multivitamin preparations from photo-oxidation; control exposure to aluminum). • If copper and manganese are removed from PN, monitor blood concentrations to prevent deficiency. • Maintain adequate hydration status to facilitate fecal and urinary excretion of bilirubin. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).

10. Serum Vitamin C (mg/dl) by Salad Intake Parenteral Nutrition-Associated Conjugated Hyperbilirubinemia in Hospitalized Infants Clinical Considerations (cont’d) • The timely initiation and advancement of enteral feeding reduces exposure to PN and helps prevent or reverse PNAC. • Once PN is discontinued, recovery and return to normal blood direct bilirubin may take months. • Participation of multidisciplinary professionals, including registered dietitians, is needed to address the challenges in planning and conducting successful studies of PNAC in hospitalized infants, that will lead to effective strategies for prevention and treatment. JOURNAL OFTHE AMERICAN DIETETICASSOCIATION Klein C, et al. J Am Diet Assoc; 2010; Volume 110 (Nov).