Chronic Liver Disease in Childhood Management of Nutrition Stuart S. Kaufman, M.D. Liver and Intestinal Transplant Program Georgetown University Transplant Institute & Children’s National Medical Center Washington, D.C. Chronic Liver Disease Malnutrition • Rapid onset in infancy • Incidence ~ 60% • Severity proportional to that of original liver disease • May accelerate hepatic decompensation Chronic Childhood Liver Diseases • Inflammation – Infection – Metabolic error • Decreased bile flow → low intestinal bile salt concentration • Fibrosis (cirrhosis) → portal hypertension Chronic Childhood Liver Diseases Infancy • • • • • Extrahepatic biliary atresia α1 - Antitrypsin deficiency Alagille syndrome Cystic fibrosis Bile acid synthetic and transport disorders Chronic Childhood Liver Diseases Childhood • • • • • α1 - Antitrypsin deficiency Cystic fibrosis Autoimmune hepatobiliary disease HIV Secondary hemochromatosis Why Does Malnutrition Develop in Chronic Liver Disease? REDUCED INTAKE!! • Anorexia – Inflammatory cytokines • Early satiety – ? Gastric compression • Hepatosplenomegaly • Ascites Why Does Malnutrition Develop in Chronic Liver Disease? Reduced Assimilation • Bile acid deficiency → lipid • Intestinal factors → all nutrients – Rapid intestinal transit – Intestinal bacterial overgrowth • Pancreatic insufficiency (CF, Alagille syndrome) → all nutrients Why Does Malnutrition Develop in Chronic Liver Disease? Increased Energy Consumption • 130 – 170 cal/kg/day for weight gain – Inefficient cellular oxidation – Vasodilatation - high cardiac output – Abdominal distention - increased work of breathing Nutrition Assessment in Chronic Liver Disease Essentials • • • • Relevant history Relevant physical examination Focused laboratory testing Potential practical ancillary studies Not Essential • REE/AEE based on formulas Nutrition-Focused History • • • • • • Liver disease status Diet: composition and quantity GI tract function Developmental milestones Medications Co-morbid disorders – Cardiac – Pulmonary – Renal Nutrition-Focused Examination • Growth parameters and anthropometry for serial assessment • Vital signs • Activity • Liver and spleen size • Edema • Skin and hair quality • Developmental milestones Laboratory Testing • Liver function: bilirubin, albumin, coagulation • Plasma iron & binding capacity • Blood vitamin & trace element levels • Plasma lipids and fatty acids • Urine calcium, zinc • Acute phase reactants Serum Albumin A Poor Nutrition Marker in Chronic Liver Disease • Increased fractional catabolic rate • Increased vascular flux • Reduces synthesis independent of nitrogen balance Ancillary Tests Relatively Available • Dual energy x-ray absorptiometry – Bone mineral density – Body composition • Indirect calorimetry - critical care setting Delivery of Nutrition Support in Progressive Liver Disease Principles • Poor nutrition independently predicts poor survival • Improving nutrition does not improve survival overall • Improving nutrition does reduce perioperative morbidity and mortality after liver transplantation Delivery of Nutrition Support in Progressive Liver Disease Principles • Low and excess nutrition undesirable • Adequate nutrition should not undermine fluid and electrolyte management Aims • Total calories for body fat in low-normal range • No routine protein restriction Delivery of Nutrition Support in Progressive Liver Disease Enteral • When low intake > malabsorption • Route – PO – mild liver disease – Tube: bolus - less appetite suppression pump - less emesis & diarrhea • Type – Dietary additives – Complete formulas Enteral Nutrition Support Principles of formula composition • MCT oil – based probably advantageous • Peptide/amino acid – based usually not advantageous, except – Hypersensitivity – Pancreatic insufficiency • Increase caloric density to minimize fluid overload Enteral Nutrition Support Practice – macronutrient goals • Total calories: 130 – 160 cal/kg/day • Protein: 3.5 – 4.0 g/kg/day • Lipid: 35 – 45% of total calories, ⅓ – ½ MCT • Density – Infants: ~ 1 cal/mL – Children: ~ 2 cal/mL Parenteral Nutrition Support Indications • Intolerance of adequate enteral energy – GI: vomiting and/or diarrhea – Renal: fluid and sodium retention Contraindications • Absolute: none, but • Hazard of central vein access with immune compromise and coagulopathy Parenteral Nutrition Support Practice – macronutrient goals • Total calories (nitrogen and non-nitrogen): ~100 – 130 cal/kg/day • Amino acid: 1.5 – 2.5 g/kg/day • Lipid emulsion: 20-25% of total calories – Query less if intestinal failure Parenteral Nutrition Support Additional concerns in chronic liver disease • Query increased free radical injury: additional selenium, cysteine, vitamin C • Query conditional carnitine and taurine deficiency • Increased urinary zinc loss • Reduced biliary copper & manganese loss Management of Nutrition in Childhood Cholestasis Stuart S Kaufman, MD Liver and Intestinal Transplantation Program Georgetown University Transplant Institute and Children's National Medical Center Washington, DC 1. Overview - Types of cholestatic liver disease affecting children A. In infants, disorders include intrahepatic and extrahepatic biliary obstruction disorders, e.g. biliary atresia, familial intrahepatic cholestasis, etc. and systemic metabolic disorders with a hepatobiliary component, e.g. cystic fibrosis. B. In older children, disorders include late onset of symptomatic 1-antitrypsin deficiency, secondary hemochromatosis, autoimmune liver diseases, and rarely, chronic hepatitis C and HIV. C. Additional considerations Time over which malnutrition develops and over which preventive or corrective measures must be taken often shorter in infants (weeks to months) than older children (months-years) Therapeutic endpoint for nutritional support is often survival to liver transplant 2. Metabolic and digestive alterations in pediatric chronic liver disease A. Final endpoint is malnutrition (body size parameters <5th percentile) i. Common = 60% incidence ii. Changes are qualitatively similar to those in adults with chronic liver diseases iii. But, abnormalities in infants and children develop and become apparent more rapidly than in adults due to higher metabolic rates associated with body growth iv. Specific contributors to malnutrition in chronic liver diseases 1. Reduced nutrient intake 2. Impaired nutrient digestion and assimilation 3. Increased energy consumption B. Reduced nutrient intake – most important i. Primary anorexia, probably CNS-effect of pro-inflammatory cytokine response to chronic liver disease ii. Increased satiety and vomiting secondary to gastric compression (ascites, hepatosplenomegaly) C. Impaired digestion and assimilation i. Bile acid deficiency with cholestatic liver disease reduces net lipid absorption from • 95% to 75%. Also, 1. Fat-soluble vitamin deficiency 2. Essential fatty acid deficiency – symptoms = dry skin and hair loss ii. Portal hypertension impairs motility and increases GI protein loss iii. Pancreatic insufficiency (Alagille syndrome, cystic fibrosis) iv. Small intestinal bacterial overgrowth; probably secondary to all of above D. Energy consumption i. Resting energy expenditures (REE) are generally increased per kg of total body weight by about 140-160% or to approximately 75 cal/kg/day in infants 1. Because the body cell compartment constitutes an increased fraction of body size 2. Because energy expenditure per unit of body cell compartment is increased ii. Active energy expenditures (AEE) are increased from usual 160% of REE to about 200% of REE (140-160 cal/kg/day in infants) 1. Because of chronically increased cardio-pulmonary expenditures (vasodilatation, hepatosplenomegaly, and ascites) 2. Because of intermittent acute inflammatory stresses E. Significance of malnutrition: predicts reduced survival after liver transplantation independent of other features of advanced liver disease i. Implication: any chronic liver disease causes malnutrition, and malnutrition, in turn, promotes further deterioration in liver function irrespective of original cause ii. Implication: Because malnutrition reflects severity of the causative liver disease, correction of malnutrition does not improve survival with a chronic liver disease unless transplantation is the primary outcome measure 3. Nutrition assessment A. Key Points of Historical Interest i. Cause and prognosis of underlying liver disease ii. Composition and trend (increasing or decreasing) in nutrient intake iii. GI function: propensity for emesis, diarrhea, and GI bleeding iv. Co-existing disorders 1. Those increasing caloric expenditures, e.g. heart and/or lung disease 2. Renal diseases that may reduce fluid and protein tolerance 3. Those disorders undermining calorie tolerance, e.g. glucose intolerance and hyperlipidemias B. Physical findings i. Height, weight, head circumference; absolute values and percentiles for age; weight for length percentile ii. Vital signs and assessment of activity, suggesting increased or decreased REE and/or AEE iii. Triceps skin fold and mid-arm muscle area and percentiles for age iv. Enlargement of liver and/or spleen v. Ascites vi. Peripheral edema C. Laboratory tests pertinent to nutrition assessment i. Serum electrolytes including calcium, phosphorus, and magnesium ii. Blood urea nitrogen and creatinine iii. Urine calcium to creatinine ratio iv. Fat soluble vitamin levels (A, 25-OH D, E) v. Prothrombin time, albumin vi. Serum zinc and urine zinc to creatinine ratio vii. Fatty acid profile, including C20:3 9 viii. ESR, C-reactive protein, ferritin ix. Iron and iron binding capacity x. Serum lipids D. Other useful studies i. DEXA for areal bone density ii. Indirect calorimetry to estimate REE when actual requirements appear to deviate from predicted 4. Objectives of pediatric nutrition support A. Deliver sufficient calories to obtain some fat stores and to insure that linear growth is not limited by nutrient supply i. While maintaining fluid and electrolyte balance (avoid fluid overload, hyponatremia, etc) ii. Without triggering other metabolic disturbance, e.g. hyperglycemia B. Prevent vitamin and trace element deficiencies that can accompany chronic liver disease (Table 1) 5. Delivering nutrition to the pediatric patient A. Enteral nutrition support i. Indication: Formula substitution for infants and supplemental products for children falling behind in growth and development on standard diet ii. Routes 1. Oral may be adequate for mild liver disease in conjunction with dietary additives a. MCT oil (7.7 cal/mL) b. Modular protein c. Glucose polymers A. Moducal - 10 cal/teaspoon B. Polycose® - 8 cal/teaspoon 2. Supplemental tube feeding a. Intermittent daytime gavage may preserve appetite but is limited by tendency to cause emesis and diarrhea b. Continuous pump infusion delivers best tolerance (minimal emesis/diarrhea) but suppresses appetite c. Nasogastric route easiest to employ and usually well-tolerated d. Gastrostomy usually contraindicated by portal hypertension e. Nasojejunal route usually impractical for protracted use iii. Enteral formulas (Table 2) 1. Infant (examples) a. Alimentum® b. Pregestimil® (diluted 0.67 – 1.0 cal/mL) 2. Child (examples) a. Pregestimil® (diluted 1.0 cal/mL) b. Peptamen Junior® c. Deliver 2.0® (diluted 1.0 – 2.0 cal/mL) iv. Macronutrient goals with enteral nutrition 1. Total calories: 130-160/kg/day 2. Protein: 3.5-4.0 g/kg/day 3. Lipid: 35-45% of total calories, 1/3 to 1/2 as MCT oil v. Practice points 1. Formulas containing MCT oil may have 25-50% better lipid absorption than those containing LCT alone 2. No advantage to peptide or amino acid formulas in absence of coexisting enteropathy or protein hypersensitivity 3. Amino acid formulas mainly for hydrolysate hypersensitivity (intolerance) 4. Infants usually tolerate formula density up to 1 cal/mL if mandated by need to restrict fluid while older children usually tolerate up to 2 cal/mL B. Parenteral nutrition support i. Indications 1. Sustained intolerance to enteral calories needed to achieve nutrient goals, e.g. a. Intractable emesis b. Intractable diarrhea c. Intractable fluid overload 2. Transient intolerance to enteral feeding because of acute critical illness resulting in ileus and/or loss of airway protection ii. Macronutrient goals 1. Total (nitrogen plus non-nitrogen calories): usually 100-130 cal/kg/day 2. Amino acid: 1.5-2.5 g/kg/day 3. Lipid emulsion: 20-25% of total calories (usually up to 3 g/kg/day) iii. Practice points 1. Advantage of parenteral over enteral nutrition in decompensated liver disease (ascites, reduced renal function) is ability to deliver a very high caloric load with easily varied macronutrient mix (based on nitrogen, triglyceride, and glucose tolerance) with relatively little fluid and sodium. 2. Disadvantages of parenteral nutrition in decompensated liver disease are dangers associated with placement and retention of a central venous catheter, particulary bleeding and infection, in patients with coagulopathy and compromised immunity 3. Although parenteral nutrition may be delivered at home, patients requiring it because of advanced liver disease usually require hospitalization 4. Cysteine may be essential in chronic liver disease; add up to 1 g/L 5. Carnitine status may be compromised, particularly with high lipid intake. If free plasma level reduced, add up to 10 mg/kg/day 6. Zinc requirement increased; add up to 0.3 mg/kg/day 7. In cholestatic patients, withhold copper and manganese and add up to selenium, 3-5 µg/kg/day and chromium, 0.2 – 0.3 µg/kg/day 8. Proprietary pediatric injectable vitamin solutions (M.V.I. Pediatric ) are adequate 9. Taurine is conditionally essential in chronic liver disease; use TrophAmine in lieu of standard amino acid solutions Table 1. Fat-soluble vitamin supplements for prophylaxis and treatment. Vitamin Brand Typical Dose Route Deficiency Comments Vitamin A Vitamin D (Calcitriol) Vitamin E (TocopherylPEGS) Vitamin K (phytonadion e) ADEKs® Pediatric Drops^ 5,000-25,000 units daily USP PO Aquasol® Parenteral A 5,000-50,000 daily for 1-2 weeks IM Rocaltrol® -Solution (1 µg/mL) -Capsules (0.25 and 0.5 µg/mL) Nutre-E-Sol®; 400 IU/15 mL ADEKs® Pediatric Drops^ 0.025 µg/kg-1.0 µg daily PO Rickets Osteomalacia 25 IU/kg/day PO Peripheral neuropathy Ataxia 2.5-5 mg daily PO Coagulopathi c hemorrhage 5-10 mg every 2 weeks SQ Mephyton® 5 mg tabs ADEKs® Pediatric Drops^ AquaMEPHYTON® Xerophthalmia (dry eye) Hyperkeratosis Night blindness Normal plasma level=300400 µg/L Symptoms @ 100 µg/L Plasma levels correlate poorly with stores-aim to maintain low levels Monitor calcium, phosphorus, intact PTH levels Desired plasma level (5-15 µg/mL) affected by serum lipids Monitor with prothrombin time (PT) Use SQ if PO ineffective ^ADEKs® Pediatric Drops include 3,170 USP units of vitamin A, 40 IU of tocopheryl-PEGS, and 0.1 mg of phytonadione per mL Table 2. Proprietary enteral formulas with MCT for chronic liver diseases. Brand Std Density (cal/mL) 1.0 1.0 Nitrogen (g/dL) Alimentum® Pregestimil® Peptamen Junior® Deliver 2.0® TwoCal HN® Elecare® Neocate Advance® MCT:LCT Amino acid (3.0) Amino acid (2.5) Lipid cals (% of total) 43 32 0.67 0.67 1.0 Hydrolysate (1.8) Hydrolysate (1.9) Hydrolysate (3.0) 48 48 33 33:67 55:45 60:40 2.0 2.0 Casein (7.4) Casein (8.4) 45 40 30:70 19:81 33:67 35:65